BACKGROUND
The contribution of the programmed death-1 (PD-1) pathway to T cell exhaustion has been thoroughly investigated in the context of chronic infections and cancers, leading to the development of potent immunotherapies. However, the role of PD-1 and its ligands, PD-L1 and PD-L2, in severe acute infections is much less appreciated.
AIM
Our objective was to utilise multiple mouse models of malaria and complementary human P. falciparum challenge studies, to investigate the role of the PD-1 pathway in acute, rapidly progressing malaria.
METHODS
We used a variety of approaches including flow cytometry, genetically modified mice, antibody blockade and adoptive cell transfers to study the roles of PD-1 and its ligands in immunity against acute, lethal disease.
RESULTS
Mechanistic studies in mice showed that PD-L1-PD-1 interactions between dendritic cells and CD4 T cells allowed rapid progression of disease resulting from uncontrolled parasite replication. Surprisingly, we found that PD-L2 was required for protection against severe, acute malaria indicating an unappreciated role for PD-L2 in counteracting the PD-1-PD-L1 axis. We utilised this finding to develop a synthetic, soluble PD-L2 protein, which was protective when administered to mice during acute malaria.
CONCLUSIONS
Overall, using malaria as a model for acute PD-1-mediated dysregulation of T cell responses, we found that the PD-L1-PD-1 interaction can have a profoundly detrimental effect on the early acquisition of protective immunity, while PD-L2 has the ability to regulate this interaction. The differential roles of the PD-1 ligands could therefore be exploited to develop next-generation immunotherapies.